On a possible mechanism of platinum resistance development in patients with advanced ovarian cancer.
Authors: Galina V. Zhukova, Elena P. Ulianova, Darya Yu. Yakubova, Aleksandr B. Sagakyants, Anna P. Menshenina, Tatiana I. Moiseenko, Ekaterina V. Verenikina, Elena Yu Zlatnik, Tatiana G. Chalabova, Alla V. Pustovalova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e17549 Background: The question of the mechanisms of platinum resistance development in advanced ovarian cancer (OC) remains open. The aim of the study was to reveal the relationship between the proliferative activity of OC cells, the disruption of apoptosis processes and the changes in the activity of transporter proteins that provide the efflux of chemotherapy drugs. Methods: Patients with advanced OC (T 3-4 N 0-3 M 0-1 ) of postmenopausal age, sensitive (SPtPs, n = 23) and resistant to platinum drugs (RPtPs, n = 17), operated on after 3-6 cycles of neoadjuvant chemotherapy, were retrospectively studied. The parameters of proliferative activity (ki67), apoptosis disturbances (p53), as well as the expression of BCRP and Pgp transporter proteins were evaluated in OC tissue using immunohistochemistry methods. Statistical analysis was performed using the Mann-Whitney and Pearson tests (χ 2 ), as well as the Spearman's rank correlation coefficient (SC). Results: In total, the dominance of the RPtPs over the SPtPs was noted in terms of intensity of the studied indicators (p &lt; 0.05-0.003), the most significant for Pgp expression. At the same time, moderate and high values of these indicators were observed in SPtPs in 42-61% of cases, which reduced the predictive value of the revealed differences. It was of interest that statistically significant correlations between the indicators in SPtPs differed from those in RPtPs. Thus, the following values of the SC were observed in SPtPs: +0.848 (ki67-p53), -0.675 (ki67-BCRP), -0.575 (p53-BCR). In RPtPs, another intensity and/or direction of these relations were noted: +0.521 (ki 67-p53), +0.500 (ki 67-BCRP), +0.705 (p53-BCR). There were no statistically significant relationships between ki67-Pgp expression in SPtPs and RPtPs. The direction and intensity of the studied relationships could indicate changes in cell regulation in primary OC in SPtPs compared to RPtPs. Thus, in SPtPs, they reflected a significant contribution of apoptotic disturbances to the enhancement of OC cell proliferation, which was limited by the negative feedback mechanism via BCRP activity suppression indicated by the presence of an inverse correlation ki67-BCRP. In RPtPs, this mechanism was apparently already lost, which resulted in a change in the direction of the statistical relationship ki67-BCRP from reverse to direct one. Under these conditions, the positive contribution of apoptosis disruption to the proliferative activity of OC cells could obviously be supplemented by a synergistic increase in the activity of the BCRP transporter protein, which removes platinum drugs from OC cells. Conclusions: Patients with advanced OC may develop platinum resistance due to discoordination of proliferation, apoptosis, and regulation of the activity of the BCRP transporter protein.